Tunable PEG-Azlactone Hydrogels Enable Programmable Multiphase Drug Delivery

New therapeutic regimens increasingly rely on coordinated, time-dependent delivery of multiple agents, placing new demands on biomaterials capable of precisely regulating release profiles. In this work, azlactone-functional polymers were cross-linked with poly(ethylene glycol) (PEG) to create a tunable hydrogel platform in which cross-linking density and PEG-diol to PEG-diamine ratio (PEG-OH:PEG-NH) regulate network stability, hydrolytic degradation, and release kinetics. Herein, we evaluate how hydrogel composition influences network characteristics, degradation behavior, and the release of structurally diverse cargos, including small molecules, proteins, and nanoparticles. Across formulations, increasing PEG-OH:PEG-NH accelerated hydrolytic degradation, while decreasing cross-linking density expanded the initial mesh, together leading to differences in release kinetics. These programmable relationships enabled phased, multicargo release of small molecules and antibodies from the same hydrogel. Together, these findings highlight PEG-azlactone hydrogels as a promising platform for programmable, phased delivery of diverse therapeutic cargos.